Discovery of novel phthalimide analogs

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a–i, 5a–f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes

Metabolomic profile, anti-trypanosomal potential and molecular docking studies of <i>Thunbergia grandifolia</i>

Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves

SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL COUMARIN DERIVATIVES AS POTENTIAL ANTIMICROBIAL AGENTS

Objective: Synthesize new series of 7-hydroxy-4-methylcoumarin and 7-alkoxy-4-methylcoumarin derivatives featuring thiosemicarbazone or thiazolidin-4-one moieties and to evaluate their antimicrobial activity against two strains of Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two Gram-negative bacteria (Escherichia Coli and Pseudomonas aeruginosa), and Candida albicans.Methods: Preparation of the new coumarin derivatives was done by adopting Pechmann condensation and attaching different isothiocyanates to give coumarin-thiosemicarbazone hybrids. Thiosemicarbazones were cyclized into thiazolidine-4-ones using chloroacetic acid or diethyl bromo malonate.Results: Compounds VIb, Xb, XIVb, and XVc gave the highest inhibition zones (&gt;20 mm) against Staphylococcus aureus. Their MIC (minimum inhibitory concentration) values ranging from 0.19-0.36 µg/ml were better than the reference drug tobramycin with MIC= 2µg/ml.Conclusion: The newly synthesized compounds with the 7-hydroxyl group showed better antimicrobial activity than those with the 7-alkoxy groups.Keywords: Coumarin, Thiosemicarbazones, Thiazolidin-4-ones, Antimicrobial activit

Quinazolinone-Amino Acid Hybrids as Dual Inhibitors of EGFR Kinase and Tubulin Polymerization

Some fluoroquinazolinones (A&ndash;H) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative G (IC50 = 0.44 &plusmn; 0.01 &micro;M) showed antitumor activity, better than that of the reference drug erlotinib (IC50 = 1.14 &plusmn; 0.04 &micro;M) against MCF-7. New derivative E (IC50 = 0.43 &plusmn; 0.02 &micro;M) showed higher activity than the reference drug erlotinib (IC50 = 2.55 &plusmn; 0.19 &micro;M) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening

Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects

A series of new fluoroquinazolinone 6&ndash;8 and 10a&ndash;g derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 &plusmn; 0.01 &micro;M), 10f (IC50 = 0.71 &plusmn; 0.01 &micro;M), 10d (IC50 = 0.89 &plusmn; 0.02 &micro;M) and 10a (IC50 = 0.95 &plusmn; 0.01 &micro;M) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 &plusmn; 0.02 &micro;M) against MCF-7. Compounds 10e (IC50 = 0.28 &plusmn; 0.02 &micro;M), 10d (IC50 = 0.38 &plusmn; 0.01 &micro;M), 7 (IC50 = 0.94 &plusmn; 0.07 &micro;M) and 10c (IC50 = 1.09 &plusmn; 0.01 &micro;M) showed better activity than the reference gefitinib (IC50 = 1.30 &plusmn; 0.04 &micro;M) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated